
Preparation of enantiomerically pure tert-leucine has remained a major challenge in process chemistry. It was obtained by the resolution of N-tosyl-DL-tert-leucine using brucine (Jaeger, D. A., et al., J. Am. Chem. Soc., 101, 717, 1979). Similarly racemic N-benzyloxycarbonyl-tert-leucine was resolved through its quinine salt (Miyazawa, T., et al., Bull. Chem. Soc. Jpn. 52, 1539, 1979). Ethyl ester of DL-tert-leucine has been resolved by crystallization of its dibenzoyl-d-tartrate salts (Jaeger, D. A., et al., ibid). Several enzymatic methods have also been reported. Hog kidney amidase was used to resolve DL-tert-leucine amide (Izumiya, N., et al., J. Biol. Chem. 205, 221-230, 1953). U.S. Pat. No. 5,219,731 describes a process where enzymatic hydrolysis of oxazolone derivative gives optically active L-tert-leucine. A similar process is reported in U.S. Pat. No. 6,180,374 using enzymatic conversion of azalactone to give chiral N-acyl derivative, which on hydrolysis results in L-tert-leucine. U.S. Patent Application 20100028959 describes a method for L-tert-leucine preparation by reductive amination of a corresponding keto compound using amino acid dehydrogenase. Direct resolution of DL-tert-leucine without any derivatization has been reported using camphor-10-sulphonic acid (Viret, J., et al., Tetrahedron Lett. 27, 5865-5868, 1986) where L-tert-leucine was obtained in about 23% yields after three recrystallizations requiring about three days. The general approach for the preparation of enantiomerically pure tert-leucine was to prepare either an ester or an amide of (DL)-tert-leucine and resolve using either enzymatic hydrolysis or by preparing salt of chiral acid or a base, followed by hydrolysis. We found this approach to be uneconomical.
The L-tert-leucine dibenzoyl-d-tartrate salt obtained during resolution has to be hydrolyzed using hydrochloric or sulphuric acid. This results in the formation of an acid salt. It is very difficult to obtain free tert-leucine from its salts because both tert-leucine and its acid salt are highly soluble in water.
Thus the methods described in the prior art are not satisfactory for industrial production. There is a need for an improved process which is simple, economical and gives both L- and D-isomers in high yields and purity. Both the isomers find application in drug design and discovery of new molecules.